Prion diseases or transmissible spongiform encephalopathies are infectious neurodegenerative diseases of humans and animals. A major feature of prion diseases is the refolding and aggregation of a normal host protein, prion protein (PrP), into a disease-associated protease-resistant form (PrPres) which may contribute to brain damage. There is a strong species barrier which prevents or delays cross-species prion infection, and this barrier mostly depends on amino acid sequence differences in the PrP of various species. For example, humans appear to be resistant to sheep scrapie in spite of extensive epidemiological evidence of exposure of humans to scrapie-infected sheep tissues. Similarly mouse-adapted sheep scrapie strains are not known to infect transgenic mice expressing human PrP, whereas these mice are susceptible to prion strains from humans with sporadic Creutzfeldt-Jakob disease. In FY16 we studied the effect of knockout of the fraktalkine receptor Cx3cr1 gene on prion disease using three scrapie strain and found no significant effect of this deletion on scrapie incubation period of disease phenotype. This result differed from previous data published by another group which showed a very slight delay in incubation period. These difference might be due to differences in the methods of assessment of disease by the observers or by differences in the background genes of the mice tested. In FY16 using stereotactic scrapie injection into the striatum, we found differences among three scrapie strains in the cell-type accumulation of disease-associated PrPSc at preclinical times after infection of mice. PrPSc from strain 22L was mainly associated with astroglia, whereas strain ME7 was mainly associated with neurons and neuropil, and strain RML was associated with both of the above patterns in different brain regions. In contrast, the patterns of early upregulation of neuroinflammatory genes were similar for all three of these scrapie strains. This result suggested that different cell-type associations of PrPSc did not induce different types of neuroinflammation. Instead similar neuronal damage by all three strain might occur resulting in similar patterns of upregulation of inflammatory genes in brain. Also in FY16 we studying the effect of human tau on prion disease in prion infected mice during development of combined amyloid and non-amyloid PrPSc deposition. In this model human tau expression did not alter disease tempo in spite of the co-deposition of abundant human tau with the mouse PrP amyloid. Thus either human tau cannot potentiate the pathogenesis of mouse prions disease or the disease in the non-amyloid form may have progressed too fast for the human tau to further accelerate the process.